Development and applications of polyglyoxylate self-immolative polymers

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Electronic Thesis and Dissertation Repository

4-20-2018 10:30 AM

Development and applications of polyglyoxylate self-immolative

polymers

Bo Fan

The University of Western Ontario

Supervisor

Gillies, Elizabeth R.

The University of Western Ontario

Graduate Program in Chemical and Biochemical Engineering

A thesis submitted in partial fulfillment of the requirements for the degree in Doctor of Philosophy

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Part of the Polymer and Organic Materials Commons

Recommended Citation Recommended Citation

Fan, Bo, "Development and applications of polyglyoxylate self-immolative polymers" (2018). Electronic Thesis and Dissertation Repository. 5293.

https://ir.lib.uwo.ca/etd/5293

This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of

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Self-immolative polymers (SIPs) are relatively recent class of stimuli-responsive and

degradable polymers that have attracted significant attention in the past several years. SIPs

consist of polymer backbones and stimuli-responsive end-caps at one or both polymer termini.

Upon detection of a stimulus, the decomposition of the end-cap leads to complete end-to-end

depolymerization. Polyglyoxylates were introduced as a new class of polyacetal based SIPs by

our group in 2014. Compared with other SIPs, polyglyoxylates have two advantages including:

1) readily available monomers and 2) low toxicity depolymerization products. These

advantages may allow polyglyoxylates to be used in a wide range of applications. This thesis

explored the design, synthesis, and study of a series of responsive end-caps for different

potential applications of polyglyoxylates. First, using the previously developed 6-nitroveratryl

carbonate end-capped poly(ethyl glyoxylate) (PEtG) that responded to UV light, it was

demonstrated that PEtG could depolymerize back to volatile monomer at ambient temperature

and pressure. This unusual feature was used to perform a facile polymer

reprogramming/recycling sequence as well as polymer patterning by a simple

irradiation-evaporation sequence. Moreover, end-caps that allowed polyglyoxylates to respond to

oxidizing and reducing conditions, acid, heat, multiple stimuli, and one that enabled

cross-linking and UV-triggered depolymerization, were developed. Furthermore, linker end-caps

were developed to conjugate PEtG with poly(ethylene glycol) to form amphiphilic block

copolymers. These copolymers were self-assembled to form nanoparticles that could load and

release payload molecules in response to stimuli. In addition, the hydrophobicity of PEtG was

tuned by copolymerization with hydrophobic monomers to improve the nanoparticle drug

loading capabilities. Lastly, triphenylmethyl end-capped PEtGs were demonstrated to undergo

temperature-dependent depolymerization. Proof-of-concept studies were performed to

demonstrate the potential of these polymers for smart packaging applications. Overall, the

work presented in this thesis serves to expand the utility of polyglyoxylate-based SIPs for

various applications through the design and synthesis of responsive end-caps and new polymer

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Keywords

Self-immolative polymer, stimuli-responsive, degradation, depolymerization, polyglyoxylate,

poly(ethyl glyoxylate), traceless, photo-lithography, amphiphilic block copolymer, micelle,

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The research described in this thesis is a result of contributions from the author as well as

coworkers and supervisor Dr. Elizabeth R. Gillies. The detailed contributions for each chapter

are as follows:

Chapter 1 and chapter 2 were written by the author and edited by Dr. Gillies.

Chapter 3 describes a project jointly conceived by the author, Dr. Gillies and postdoctoral

fellow Dr. John F. Trant. The author conducted most of the depolymerization studies with

assistance from Rebecca E. Yardley and Andrew J. Pickering. The photo-patterning study was

conducted with assistance from Dr. Franç ois Lagugné-Labarthet and the Western

Nanofabrication Facility. The manuscript was prepared by the author and was revised with the

assistance of Dr. Gillies and Dr. Trant.

Chapter 4 describes work jointly conceived by the author and Dr. Gillies, with additional

acid-sensitive end-caps contributed by Dr. Trant. The author conducted most of synthesis (except

for the acid-sensitive end-caps), all characterization, and all depolymerization studies. The

manuscript was prepared by the author and was revised with the assistance of Dr. Gillies.

Chapter 5 describes work jointly conceived by the author and Dr. Gillies. The author conducted

all the experiments. The manuscript was prepared by the author and was revised with the

assistance of Dr. Gillies.

Chapter 6 describes work jointly conceived by the author, Dr. Gillies and Dr. Trant. The author

conducted most of the synthesis, characterization, and all depolymerization studies. Dr. Trant

contributed the synthesis of menthyl glyoxylate, Rebecca Yardley conducted the synthesis of

butyl glyoxylate, and Aneta Borecki conducted the cell studies. The manuscript was prepared

by the author and was revised with the assistance of Dr. Gillies.

Chapter 7 describes work jointly conceived of by the author, Dr. Trant, Dr. Gillies, and

collaborator Dr. Olivier Sandre. Dr. Trant conducted the synthesis of end-caps while the author

conducted the synthesis of polymers and all depolymerization studies. The synthesis of iron

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prepared by the author and Gauvin Hemery and was edited by Dr. Gillies and Dr. Sandre.

Chapter 8 describes work jointly conceived of by the author, Dr. Gillies and Dr. Romulo

Salazar. The author conducted all synthesis, characterization, and polymer film colour change

studies. The polymer film depolymerization studies were conducted by Dr. Salazar. The

manuscript was prepared by the author and was revised with the assistance of Dr. Gillies.

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First of all, I would like to give my sincere appreciation to my supervisor Dr. Gillies. I thank

her for accepting me as a member of this caring, mutually helping and creative research group.

More importantly, I want to acknowledge Dr. Gillies for her guidance and encouragement

along the way, without whom this thesis would not be achievable.

My thanks would also go to all the previous and present members of the Gillies group. Thank

you all for creating a caring and mutually helping research environment. You leave me with

lots of unforgettable memories during the past several years.

I also would like to thank my thesis examiners, Dr. Xu, Dr. Zhang, Dr. Gilroy and Dr. Gu for

taking time to read through my thesis. Many thanks to all the faculty and staff in the

Department of Chemical and Biochemical Engineering and the Department of Chemistry for

their support in my study and research.

Furthermore, I would like to express heartfelt appreciation to my girlfriend-Jing Wan who has

been supportive for my all decisions. I also want to thank her for reading through this thesis.

Lastly but not the least, I want to give the deepest thanks to my parents, without the constant

love, supporting and encouragement from both of you, nothing will be possible for me.

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Abstract ... i

Co-Authorship Statement... iii

Acknowledgments... v

Table of Contents ... vi

List of Tables ... x

List of Figures ... xi

List of Schemes ... xix

List of Abbreviations ... xxi

Chapter 1 ... 1

1 Introduction ... 1

1.1 Overview ... 1

1.2 Research objectives ... 3

1.3 Thesis outline ... 4

1.4 References ... 6

Chapter 2 ... 9

2 Stimuli-responsive polymers (SRPs) ... 9

2.1 General non-degradable SRPs ... 10

2.1.1 Light-responsive polymers... 10

2.1.2 Thermo-responsive polymers ... 14

2.1.3 pH-responsive polymers ... 15

2.1.4 Gas-responsive polymers ... 17

2.2 Stimuli-responsive and degradable polymers ... 19

2.2.1 Acid-degradable polymers ... 20

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2.2.4 Limitations of conventional stimuli-responsive and degradable polymers

... 24

2.3 Self-immolative polymers ... 25

2.3.1 SIPs depolymerizing via elimination reactions ... 26

2.3.2 SIPs depolymerizing via cyclization reactions ... 30

2.3.3 SIPs depolymerizing due to low-ceiling temperature ... 34

2.3.4 Applications of SIPs in drug delivery ... 41

Chapter 3 ... 55

3 Photo-controlled depolymerization of stimuli-responsive poly(ethyl glyoxylate): Differentiating features and traceless ambient depolymerization ... 55

3.1 Introduction ... 55

3.2 Experimental section ... 56

3.3 Results and discussion ... 61

3.4 Conclusions ... 70

Chapter 4 ... 76

4 End-capping strategies for triggering end-to-end depolymerization of polyglyoxylates ... 76

4.3.1 Development of redox-responsive PEtG ... 87

4.3.2 Development of acid-responsive PEtG ... 94

4.3.3 Development of a multi-responsive end-cap ... 96

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Chapter 5 ... 114

5 Poly(ethyl glyoxylate)-poly(ethylene glycol) nanoparticles: Stimuli-responsive drug release via end-to-end polyglyoxylate depolymerization ... 114

5.3.1 Synthesis of stimuli-responsive PEtG-PEG triblock copolymers ... 125

5.3.2 Self-assembly of PEtG-PEG triblock copolymers in aqueous solution .. 131

5.3.3 Stimuli-responsive properties of the nanoparticles ... 132

5.3.4 Encapsulation and triggered release of drugs and model drugs ... 139

Chapter 6 ... 151

6 Tuning the hydrophobic core of self-immolative polyglyoxylate assemblies ... 151

6.3.1 Polymer synthesis ... 161

6.3.2 Celecoxib loading and release ... 169

6.3.3 In vitro toxicity studies ... 173

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Chapter 8 ... 204

8 Temperature-dependent depolymerization of trityl end-capped poly(ethyl glyoxylate): potential applications in smart packaging ... 204

8.2 Experimental section. ... 206

8.3 Results and discussion. ... 211

8.4 Conclusions. ... 219

8.5 References. ... 220

Chapter 9 ... 224

9 Conclusions and future perspectives ... 224

Appendix 1: Permission to reuse copyrighted material in Chapter 1 ... 228

Appendix 2: Permission to reuse copyrighted material in Chapter 2 and published chapters ... 229

Appendix 3: Supporting information for Chapter 3 ... 235

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Table 4.1 Molar mass and thermal properties of end-capped PEtGs and measured by SEC,

TGA, and DSC. ... 90

Table 5.1 Properties of PEtG with different linker end-caps and PEG-PEtG-PEG copolymers.

These polymers have been previously reported. ... 129

Table 5.2 Hydrophilic mass fractions (f) of the block copolymers and corresponding

characterization of self-assembled nanoparticles by DLS and CAC measurement. Errors on

the measurements correspond to the standard deviations. ... 131

Table 6.1 SEC and thermal analysis results for the polymers. From SEC; From TGA;From

DSC; From previously published work. ... 163

Table 6.2 Characterization data for the amphiphilic block copolymers and their resulting

assemblies. Previously reported; From SEC; Measured at 1 mg/mL of copolymer. ... 166

Table 6.3 Characterization data for the block copolymer assemblies. Previously reported. 168

Table 6.4 Size characterization and celecoxib loading data for the block copolymer

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Figure 1.1 Structure of polyglyoxylates and the depolymerization mechanism after end-cap

Chemical Society.) ... 3

Figure 2.1 Schematic representations of SRPs: a) General non-degradable SRPs that change

in physical properties in response to a stimulus; b) SRPs that can entirely degrade in response

to a stimulus stoichiometrically; c) Self-immolative polymers (SIPs) as a sub-class of SRPs

that can depolymerize in response to a stimulus in an amplified manner. ... 9

Figure 2.2 Representative light-responsive molecules applied in stimuli-responsive polymers:

a) Cis-trans transformation of aromatic azo compounds, b) hydrophobic spiropyran to

hydrophilic merocyanine transformations under different wavelengths of light. ... 11

Figure 2.3 a) Synthesis procedure for the azobenzene liquid crystalline polymer network; b)

Schematic and c) photographs showing light-driven forward moving of a “vehicle” equipped

with a spring-like “motor”. (Reproduced with permission from reference (12). Copyright

2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) ... 12

Figure 2.4 Photochromic polymersomes exhibiting photo-switchable and reversible bilayer

Figure 2.5 Chemical structures of some typical thermo-responsive polymers. ... 14

Figure 2.6 a) Temperature dependence of water and oil contact angles for a

PMMA-b-PNIPAM film; b) Reversible water and oil contact angle transition of block copolymer film

at different temperatures; c) Diagram of reversible formation of intermolecular hydrogen

bonding between PNIPAM chains and water below and above the LCST. (Reproduced with

Weinheim.)... 15

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conformation and behavior of QD-GO at a given pH value. (Reproduced with permission

Figure 2.9 Schematic illustration of: a) Preparation of P(DMAEMA-co-CMA) single-chain

nanoparticles through intrachain photo-cross-linking and the gas-switchable size change of

nanoparticle in aqueous solution; b) Preparation of tadpole-like PS-b-P(DMAEMA-co-CMA)

nanoparticles and their gas-responsive self-assembled micellar assemblies. (Reproduced with

Figure 2.10 Common acid-degradable functional groups and their degradation products. .... 20

Figure 2.11 Polyurethane containing acid-sensitive ketal groups in polymer backbone. ... 21

Figure 2.12 Chemical structure of poly(disulfide) with incorporation of paclitaxel via a PEG

Figure 2.13 Chemical structure of oxidation-responsive polymer and the particle degradation

mechanism in response to H2O2. (Reproduced with permission from reference (52).

Figure 2.14 a) Synthesis of a photo-degradable amphiphilic block copolymer containing

ortho-nitrobenzyl photolabile groups; b) Schematic illustration of a photo-degradable

Figure 2.15 Synthesis of a poly(benzyl carbamate)-based SIP and its depolymerization

mechanism following end-cap removal. ... 27

Figure 2.16 Modification of poly(benzyl carbamate) SIP via backbone structures and end-cap

design. ... 28

Figure 2.17 Chemical structure and depolymerization mechanism of poly(benzyl ether)s, and

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elimination and decarboxylation reactions, and stimuli-responsive end-caps installed on this

category of SIPs. ... 31

Figure 2.19 SIPs that depolymerize via cyclization and elimination reactions: a) Replacement

of the carbamate from Figure 2.18 with a carbonate leads to faster depolymerization; b)

Replacement of the amine nucleophile in Figure 2.18 with a thiol leads to even faster

depolymerization; c) An SIP that depolymerizes entirely through a series of cyclization

reactions. ... 32

Figure 2.20 Depolymerization profile for linear SIPs involving an initial pseudo zero-order

domain followed by a gradual transition toward first-order behavior. (Reproduced with

Figure 2.21 General synthesis and depolymerization of polyacetals. ... 34

Figure 2.22 Synthesis and end-capping of PPA... 35

Figure 2.23 A patterned film that reveals a cylindrical hole when exposed to the

corresponding stimulus: a) Patterned plastic film design strategy; b) Photograph of the film

before stimulus; c) Photograph of the film after 15 min of exposure to stimulus. (Reproduced

Figure 2.24 a) Schematic illustration for the preparation of PPA microcapsules by a flow

focusing microfluidic technique; b) SEM images of microcapsules before and after exposure

Figure 2.25 Synthesis and end-capping of PEtG-based SIPs. ... 41

Figure 2.26 a) Chemical structure of an amphiphilic polycarbamate-b-PEG; b) TEM image of

particles formed from this polymer; c) Nile red release from the particles over time as

measured by fluorescence spectroscopy. (Reproduced with permission from reference (72).

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and reduction-responsive linkers and their self-assembly into vesicles. (Reproduced with

Figure 2.28 Chemical structure of an amphiphilic PEG-PEtG-PEG triblock copolymer; b)

TEM image of micelles formed from this polymer; c) Micelle disintegration study as

measured by 1H NMR in response to UV irradiation. (Reproduced with permission from

Figure 3.1 Mass loss profiles for UV light irradiated (I) and non-irradiated (N-I)

PEtG-NVOC coatings under different conditions: a) 150 m thickness immersed at 20 o_{C in buffers}

of pH 3-8; b) 150 m thickness immersed at varying temperatures in pH 7.0 buffer; c)

Varying film thicknesses from 25-150 m immersed in pH 7.0 buffer at 20 o_{C; d) 150}_m

thickness immersed in soil with either 10, 20 or 30 mass % of pH 7.0 buffer at 20 oC; e) Film

thicknesses of 50 or 150 m in air (no aqueous immersion) at either 20 or 30 oC; f) Film

thicknesses of 50 or 150 m in air either exposed or not exposed to sunlight in a greenhouse.

In each experiment, the error bars represent the standard deviation of the measurements for

three samples. ... 63

Figure 3.2 a) Number average molar mass (Mn) of polymer remaining on the coating during

the mass loss study, as measured by SEC.; b,c) SEM images of the polymer coating after 5

days of immersion in 0.1 M, pH 7.0 phosphate buffer at 20 °C b) control without UV

irradiation and c) with UV irradiation. ... 65

Figure 3.3 Collection of depolymerized ethyl glyoxylate monomer over time after irradiation

of PEtG-NVOC and the corresponding experimental set-up. ... 68

Figure 3.4 Digital optical microscopy of ambient self-developed patterns: The metal masks

are shown in a) and b) while the corresponding 500 m and 20 m reservoirs fabricated from

these masks are shown in c) and d) respectively. ... 70

Figure 4.1 Schematic illustrating the end-cap cleavage and depolymerization process for

PEtG. ... 78

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and at various time points after H2O2 addition (spectra are offset to allow the progression

over time to be clearly observed); b-d) Percent depolymerization versus time in the presence

and absence of stimuli for b) PEtG-boronate with H2O2, c) PEtG-disulfide-a with DTT, and

d) PEtG-azobenzene with DTT. In each case, PEtG-control was also exposed to the stimulus

to confirm that the cleavage was specific to the end-cap. ... 92

Figure 4.4 Percent depolymerization versus time for a) PEtG-MMT and b) PEtG-DMT in the

absence and presence of varying concentrations of acetic acid. ... 96

Figure 4.5 Depolymerization versus time for PEtG-multi following exposure to UV light,

H2O2, Zn/acetic acid, and combinations of these stimuli. ... 99

Figure 4.6 1H NMR spectrum (400 MHz, 9:1 CD3CN:D2O) of PEtG-cross-linked a) before

and b) after UV irradiation. Note that peaks corresponding to derivatized cross-linker 16 are

not visible because assuming a 1:1 ratio of PEtG:16 in the network, there would be >100

EtGH molecules per derivatized 16. ... 101

Figure 4.7 a-b) SEC traces (RI detection) for a) PEtG-disulfide-a and b) PEtG-disulfide-b

following different sonication times; c) Changes in Mn for disulfide-a and

PEtG-disulfide-b following different sonication times. ... 104

Figure 5.1 Depolymerization of PEtG to ethyl glyoxylate (EtG), hydration to form ethyl

glyoxylate hydrate (EtGH), and hydrolysis to glyoxylic acid (GA) and ethanol. ... 116

Figure 5.2 Chemical structures of linker end-caps each containing a chloroformate, one or

more stimuli-responsive moieties, and a site for conjugation of PEG. ... 126

Figure 5.3 TEM images of nanoparticles formed from a) disulfide-PEG, b)

PEtG-nitrobenzyl-PEG, c) PEtG-boronate-PEG, and d) PEtG-multi-PEG. ... 132

Figure 5.4 Stimuli-responsive properties of PEtG-disulfide-PEG nanoparticles: a) % Initial

count rate versus time (measured by DLS) for nanoparticles exposed to varying

concentrations of DTT, b) % Depolymerization versus time for PEtG-disulfide-PEG

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disulfide-PEG nanoparticles in the same solvent. Peaks corresponding to the

depolymerization products EtGH and the DTT adduct appear after the addition of 10 mM

DTT. ... 135

Figure 5.5 %Initial count rate, measured by DLS, versus time for nanoparticles and their

corresponding controls with or without stimuli: a) PEtG-nitrobenzyl-PEG nanoparticles with

UV light, b) PEtG-boronate-PEG with H2O2, c) PEtG-multi-PEG with H2O2, UV light, or

both. The study was carried out at pH 7.4, except for b) which was also performed at pH 5.0.

The temperature was 37 °C. Error bars represent the standard deviation on 3 samples. ... 137

Figure 5.6 Change in Nile red fluorescence intensity as an indicator of its release from

nanoparticles composed of a) disulfide-PEG, b) boronate-PEG, and c)

PEtG-nitrobenzyl-PEG in the presence and absence of their corresponding stimuli. Error bars

correspond to the standard deviation on three samples. ... 141

Figure 5.7 Release of Dox from PEtG-nitrobenzyl-PEG nanoparticles with and without UV

irradiation at a) pH 7.4 and b) pH 5.0. ... 142

Figure 5.8 Curcumin retention in a) PEtG-disulfide-PEG and b) PEtG-boronate-PEG

nanoparticles in the presence and absence of stimuli as well as their corresponding controls.

... 143

Figure 6.1 Chemical structure of the monomers used in this chapter ... 161

Figure 6.2 TEM images of particles formed from a) PEG2000; b)

PEtBuG-PEG5000; c) PEtMenG-PEG2000; d) PMenG-PEG750; e) PEG2000; f)

PEtGC-PEG5000. ... 168

Figure 6.3 Depolymerization of particles following UV light irradiation (or no light for

controls), monitored by DLS based on count rate. ... 169

Figure 6.4 Release of celecoxib over time for assemblies irradiated with UV light and for the

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irradiation and b) after UV irradiation. ... 173

Figure 7.11H NMR spectra of PEtG-DA-Bn incubated in 9:1 CD3CN:D2O at 75 C. Spectra

are offset to allow the progression over time to be clearly observed. ... 195

Figure 7.2 a) Depolymerization of polymers in 9:1 CD3CN:D2O monitored by NMR

spectroscopy; Assembly degradation in pH 7.4 phosphate buffer monitored by b) DLS count

rate changes, c) Nile red fluorescence changes, and d) NMR spectroscopy. ... 196

Figure 7.3 TEM images of a) PEtG-DA-PEG750 vesicles, b) PEtG-DA-PEG5000 micelles,

c) unloaded IONPs, d) IONP-loaded PEtG-DA-PEG5000 micelles. ... 197

Figure 7.4 Bulk temperature, particle diameter, and count rate measured before, during, and

after magnetic hyperthermia using an in situ DLS for 35 mass% IONP-loaded a)

PEtG-DA-PEG5000 micelles and b) Micelle-control. ... 198

Figure 8.1 Structures of trityl end-capped PEtG. ... 205

Figure 8.2 Chemical structure of PEtG-control. ... 213

Figure 8.3 Mass loss profiles for end-capped PEtGs at different temperatures: a) PEtG-DMT;

b) PEtG-MMT; c) PEtG-AMT; d) PEtG-AT; d) PEtG-control. In each experiment, the error

bars represent the standard deviation of the measurements for three samples. ... 214

Figure 8.4 Variable temperature 1_{H NMR spectra of a) PEtG-AMT and b) PEtG-control at}

different temperatures (15 min per temperature increment unless otherwise indicated).

Spectra are offset to allow the progression over time to be clearly observed. ... 215

Figure 8.5 Mechanism for temperature dependent depolymerization of trityl-capped PEtG.

... 216

Figure 8.6 a) and b) Color changes of different PEtG coatings containing either a) 0.1 wt%

Nile red or b) 0.5 wt% IR-780 incubated at 22 °C for different time periods. The rectangular

color patches are computer generated color samples that were sub-sampled from digital

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for 24 h, the inserted pictures in c) are polymer coatings before and after incubation. ... 218

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Scheme 3.1 Chemical structure of PEtG-NVOC and its UV light-initiated depolymerization.

This is followed by hydrate formation and hydrolysis of the resulting ethyl glyoxylate in the

presence of water. ... 62

Scheme 4.1 Synthesis of chloroformate end-caps 4 - 6. ... 89

Scheme 4.2 Synthesis and end-capping of PEtG. ... 89

Scheme 4.3 Synthesis of multi-responsive end-cap 11. ... 97

Scheme 4.4 Synthesis of cross-linkable end-cap 15. ... 100

Scheme 4.5 Cross-linking of PEtG-trialkene and UV light triggered depolymerization of the resulting PEtG-cross-linked. ... 101

Scheme 5.1 Synthesis of end-cap 3. ... 127

Scheme 5.2 Synthesis of end-cap 4. ... 127

Scheme 5.3 Synthesis of end-capped PEtGs... 128

Scheme 5.4 Synthesis of PEG-PEtG-PEG copolymers a) PEtG-disulfide-PEG, b) PEtG-nitro-PEG, c) PEtG-boronate-PEtG-nitro-PEG, and d) PEtG-multi-PEG... 130

Scheme 6.1 Synthesis of polymers: a) PEtBuG; b) PMenG; c) PEtMenG; d) PEtGC. ... 163

Scheme 6.2 Synthesis of block copolymers via coupling of PEG-N3 with a) PEtBuG; b) PMenG; c) PEtMenG; d) PEtGC. ... 165

Scheme 7.1 Proposed cap cleavage and depolymerization mechanism of PEtG end-capped with a DA adduct (PEtG-DA). ... 183

Scheme 7.2 Synthesis of end-caps 4a and 4b. ... 193

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methoxy groups. ... 212

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AIBN 2,2’azobis(2-methylpropionitrile)

ATR Attenuated total reflectance

Bu Butyl

BuG Butyl glyoxylate

Boc tert-butyloxylcarbonyl

BSA Bovine serum albumin

C Chloral

CuAAC Copper-assisted azide-alkyne cycloaddition

CR Counter rate

CAC Critical aggregation concentration

Cur Curcumin

DBTL Dibutyltin dilaurate

DA Diels-Alder

DLS Dynamic light scattering

DSC Differential scanning calorimetry

DEG Di(ethylene glycol)

DMEM Dulbecco’s modified eagle medium

Dox Doxorubicin

DTT Dithiothreitol

DMAP 4-Dimethylaminopyridine

DMF N, N’-Dimethylformamide

DMSO Dimethyl sulfoxide

Đ Dispersity

EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

EI Electron impact

ESI Electrospray mass spectrometer

Et Ethyl

EtG Ethyl glyoxylate

EtGH Ethyl glyoxylate hydrate

FBS Fetal bovine serum

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GA Glyoxylic acid

GO Graphene oxide

HRMS High-resolution mass spectrometry

IONPs Iron oxide nanoparticles

LCST Lower critical solution temperature

Me Methyl

MenG L-menthyl glyoxylate

MFH Magnetic field hyperthermia

Mn Number average molecular weight

Mw Weight average molecular weight

MWCO Molecular weight cut-off

MSDS Material safety data sheets

NMDEA N-methyldiethanolamine

NEt3 Triethyl amine

NMR Nuclear magnetic resonance

NIR Near-infrared

NVOC 6-Nitroveratryloxycarbonyl

NVOC-Cl 6-Nitroveratryloxycarbonyl chloride

OPA o-phthalaldehyde

PAA Poly(acrylic acid)

PBuG Poly(butyl glyoxylate)

PDI Polydispersity index

PDMAEMA Poly(dimethylaminoethyl methacrylate)

PDMA Poly(N,N’-dimethylacrylamide)

PE Polyethylene

PEtG Poly(ethyl glyoxylate)

PEtBuG Poly[(ethyl glyoxylate)-co-(butyl glyoxylate)]

PEtGC Poly[(ethyl glyoxylate)-co-chloral]

PEtMenG Poly[(ethyl glyoxylate)-co-(menthyl glyoxylate)]

PEG Poly(ethylene glycol)

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PMeG Poly(methyl glyoxylate)

PMenG Poly(menthyl glyoxylate)

PMA Poly(methyl acrylate)

PMMA Poly(methyl methacrylate)

PNIPAM Poly(N-isopropylacrylamide)

PPA Poly(phthalaldehyde)

PS Polystyrene

PTEGMA Poly[tri(ethylene glyocol) monoethyl ether methacrylate]

P2VP Poly(2-vinylpyridine)

PVS Poly(vinyl sulfone)

QDs Quantum dots

RAFT Reversible addition-fragmentation chain transfer

ROS Reactive oxygen species

SANS Small angle neutron scattering

SEC Size exclusion chromatography

SEM Scanning electron microscopy

SIPs Self-immolative polymers

SRPs Stimuli-responsive polymers

TBDMS tert-butyldimethylsilyl

TGA Thermogravimetric analysis

THF Tetrahydrofuran

TEM Transmission electron microscopy

To On-set degradation temperature

Tc Ceiling temperatures

Tg Glass transition temperature

Tm Melting point temperature

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Chapter 1

1

Introduction

1.1 Overview

Polymers are large molecules composed of many repeating units linked together via

covalent bonds. They can be natural, such as polysaccharides, proteins, and nucleic acids,

or synthetic, such as polyethylene (PE), polystyrene (PS), and nylon.1 Their high molar

mass provides polymers with properties that are significantly different from small

molecules.2 In addition, the physical properties of polymers can be tuned significantly to

achieve specific functions by changing the chemical structures of the polymer backbones

and side groups, as well as their molecular weight, branching, or tacticity.2_{For example,}

PE is one of the most commonly encountered plastics in our daily lives. Depending on the

molecular weight or chain branching, its physical properties change dramatically.

Ultra-molecular-weight polyethylene has a yield strength that is comparable with

high-strength steels, therefore it can be used in bulletproof vests.3 However, low-density

polyethylene, which contains a high degree of branching, is more frequently used in

packaging due to its low tensile strength.4

Since the first successful commercialization of the thermoplastic polymer-Nylon,5 by

Wallace Carothers at Dupont’s research facility in 1935, polymeric materials have offered

great possibilities for the development of human society in the past century. A series of

polymeric materials have been successfully commercialized in 1940s-1980s.6 However,

since the 1990s, a significant amount of research effort has shifted to polymeric materials

that can respond to their environmental conditions or external stimuli. These polymers are

usually referred to as stimuli-responsive polymers (SRPs) or “smart” polymers.7 SRPs can

receive external signals and exhibit responses by changing their physical properties, such

as shape, color, solubility, and even chemical structure (e.g., cleavage of side groups or

polymer backbone). The chemical or physical property changes associated with SRPs

endow them with a series of novel applications that cannot be achieved by traditional

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including biosensors,8_{smart coatings,}9_{drug delivery vehicles,}10-12_{self-healing,}13_and

shape-memory materials.14_{However, conventional SRPs usually need significant amounts}

of stimuli for a clear response, and one specific polymer backbone can usually respond to

only one stimulus.15 These limitations create a bottleneck for the applications of many

current SRPs.

Self-immolative polymers (SIPs), are a new class of SRPs. They consist of a polymer

backbone and a stimuli-responsive end-cap at one (or both) polymer termini.16-17 Once the

end-cap detects an external signal, the decomposition of the end-cap leads to complete

collapse of the polymer backbone via end-to-end depolymerization. Therefore, compared

with traditional stimuli-responsive polymers, SIPs can easily achieve responsiveness to a

series of different stimuli via changes in the end-cap rather than completely re-engineering

a new polymer backbone. Via this simple strategy, SIPs that respond to light,18-19 heat,20

pH,21 ultrasound,22 oxidizing and reducing conditions,23 and chemicals24 have been

developed. In addition, the response structure of SIPs allows signal amplification, as one

equivalent of stimulus can lead to complete polymer depolymerization and the generation

of hundreds and even thousands of monomers or depolymerization products. In the past l0

years, SIPs including polycarbamates, polycarbonates, poly(benzyl ether)s, and polyacetals

have been reported.15, 25-26However, many of these SIPs produce toxic depolymerization

products such as quinone methides27_{or o-phthalaldehyde,}28_{which may hinder their use in}

some applications.

Polyglyoxylates (PGs) were introduced by our group as a new class of polyacetal-based

SIPs in 2014 (Figure 1.1).29_{PGs can be readily prepared from inexpensive commercially}

available glyoxylates such as ethyl glyoxylate or from other simple glyoxylates prepared

from readily available starting materials such as maleic or fumaric acid via ozonolysis of

the corresponding diesters. Following depolymerization, PGs ultimately degrade to the

alcohol and glyoxylic acid, a metabolic intermediate in the important glyoxylate cycle.30

This is an anabolic variant of the tricarboxylic acid cycle that occurs in plants, bacteria,

protists, and fungi. Glyoxylic acid is also a metabolic byproduct of mammalian

(27)

suggesting that the depolymerization products of poly(ethyl glyoxylate) (PEtG) are well

tolerated in the environment by plants and in mammalian models.32_{The innocuousness of}

these depolymerization products position PGs as ideal materials for applications in vivo or

in the environment.

Figure 1.1 Structure of polyglyoxylates and the depolymerization mechanism after

American Chemical Society.)

1.2 Research objectives

Our group has previously reported the synthesis of a small number of different alkyl and

benzyl polyglyoxylates end-capped with a UV-responsive trigger.29 We also prepared

amphiphilic block copolymers of triggerable hydrophobic poly(ethyl glyoxylate) PEtG

with hydrophilic poly(ethylene glycol) (PEG) and showed that these materials

self-assembled into micelles. Furthermore, when the micelles were exposed to UV light, the

hydrophobic block depolymerized, decomposing the micelle.26 This PG-based

UV-responsive SIP had a fast depolymerization rate in solution. However, its depolymerization

profiles in the solid state under different conditions, such as different pHs, temperatures,

coating thicknesses, and even different environmental media, should be explored for

practical applications. In addition, the UV-responsive PGs may find application in fields

where UV light can be used as a trigger, such as agricultural materials and industrial

photolithography. However, for applications such as drug delivery, UV-responsive SIPs

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Therefore, this thesis aims to expand the applications of polyglyoxylate-based SIPs by

increasing the flexibility of the triggering stimuli initiating decomposition by incorporating

different end-caps capable of responding to additional environmental cues besides UV

light. As an extension of this, the self-assembly of PG-based amphiphilic block copolymers

into nano-carriers (such as micelles and vesicles) for on-demand drug release has also been

explored.

1.3 Thesis outline

The thesis is divided into 9 chapters. A broad literature review of all classes of SRPs is

presented in Chapter 2. Following the review, Chapter 3-8 will describe six projects

towards the synthesis, modifications and applications of PG based self-immolative

polymers. The projects details are as follows.

Chapter 3 describes the solid-state depolymerization of UV-sensitive PEtG under different

conditions. This thesis chapter will explore the effects of different environmental

conditions such as pH, temperature, and coating thickness on the depolymerization of PEtG

coatings with the aim to fully understand the depolymerization process in the solid state

and thus understand potential applications of these materials as coatings.

Chapter 4 includes work aimed at increasing the flexibility of the triggering stimuli

initiating decomposition by incorporating different end-caps. New stimuli include

biologically relevant signals such as changes in the concentrations of oxidizing or reducing

agents. An oxidation-sensitive end-cap incorporating a pinacol borane that cleaves in the

presence of hydrogen peroxide and a reduction-sensitive disulfide end-cap that cleaves in

the presence of biologically relevant thiols that would be appropriate for targeting the

reductive environments of cancer tumors were prepared and studied. Novel

multi-responsive end-caps that respond to very different stimuli including combinations of UV

light, hydrogen peroxide, and reducing conditions simultaneously will be introduced.

Furthermore, a cross-linker end-cap that allows SIPs to form cross-linked networks while

at the same time depolymerizing in response to external stimuli, such as UV light will also

(29)

Chapter 5 explores the development and application of PG-based nano-assemblies. New

linker end-caps allowed different stimuli-responsive PEtGs to form amphiphilic block

copolymers that were capable of self-assembling to form nano-sized particles in aqueous

solution. Specifically, based on the multi-responsive PEtGs in Chapter 4, the design,

synthesis and self-assembly of H2O2, reduction, and dual-responsive (both UV light and

H2O2) micelles will be described. The signal amplification properties of PEtGs was also

explored in this context. Moreover, loading of anti-cancer drugs into PG-based

nano-carriers and their release in response to stimuli were examined. This work will expand the

applications of PEtG-baseds SIPs into the biomedical field for the release of drugs and

other molecules on demand.

Chapter 6 explores different monomer combinations to increase the hydrophobicity of

PG-based particles and thereby improve their hydrophobic drug loading capabilities.

Specifically, ethyl glyoxylate was copolymerized with n-butyl glyoxylate, choral, and

menthol glyoxylate, respectively, and these monomers were also polymerized to form

hydrophobic homopolymers. These PGs were further coupled with hydrophilic PEG to

form amphiphilic block copolymers. The loading capabilities of the nanoparticles formed

from these copolymers were examined by incorporation of the hydrophobic

drug-celecoxib.

Chapter 7 introduces the design and synthesis of a new generation of thermo-responsive

end-caps based on Diels-Alder adducts that allow SIPs to depolymerize in response to

environmental temperature changes. Furthermore, self-assembly and disassembly of

thermo-responsive micelles and vesicles formed from these polymers in response to direct

and indirect heat were also explored.

Chapter 8: This Chapter explores the temperature dependent depolymerization properties

of triphenylmethyl end-capped PEtG films, and their potential applications in smart

packaging.

Finally, a general discussion with conclusions outlining the significance, limitations and

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1.4 References

(1) Gao, Y.; Wei, M.; Li, X.; Xu, W.; Ahiabu, A.; Perdiz, J.; Liu, Z.; Serpe, M. J.

Stimuli-responsive polymers: Fundamental considerations and applications. Macromol.

Res. 2017, 25, 513-527.

(2) Stein, R. S.; Tobolsky, A. V. An investigation of the relationship between polymer

structure and mechanical properties: Part I: relationship between structure, mechanical

properties, and birefringence. Text. Res. J. 1948, 18, 201-223.

(3) Kelly, J. M. Ultra-high molecular weight polyethylene. J. Macromol. Sci., Polym. Rev.

2002, 42, 355-371.

(4) Raj, B. Low density polyethylene/starch blend films for food packaging applications.

Adv. Polym. Technol. 2004, 23, 32-45.

(5) Kauffman, G. B. Wallace Hume Carothers and nylon, the first completely synthetic

fiber. J. Chem. Educ. 1988, 65, 803-808.

(6) Brandrup, J.; Immergut, E. H.; Grulke, E. A.; Abe, A.; Bloch, D. R., Polymer

Handbook. Wiley New York etc: 1989; Vol. 7.

(7) Stuart, M. A. C.; Huck, W. T.; Genzer, J.; Müller, M.; Ober, C.; Stamm, M.;

Sukhorukov, G. B.; Szleifer, I.; Tsukruk, V. V.; Urban, M. Emerging applications of

stimuli-responsive polymer materials. Nat. Mater. 2010, 9, 101-113.

(8) Hu, J.; Liu, S. Responsive polymers for detection and sensing applications: current

status and future developments. Macromolecules 2010, 43, 8315-8330.

(9) Nath, N.; Chilkoti, A. Creating “smart” surfaces using stimuli responsive polymers.

Adv. Mater. 2002, 14, 1243-1247.

(10) Mura, S.; Nicolas, J.; Couvreur, P. Stimuli-responsive nanocarriers for drug delivery.

Nat. Mater. 2013, 12, 991-1003.

(11) Ganta, S.; Devalapally, H.; Shahiwala, A.; Amiji, M. A review of stimuli-responsive

nanocarriers for drug and gene delivery. J. Controlled Release 2008, 126, 187-204.

(12) Cabane, E.; Zhang, X.; Langowska, K.; Palivan, C. G.; Meier, W. Stimuli-responsive

polymers and their applications in nanomedicine. Biointerphases 2012, 7:9.

(13) Habault, D.; Zhang, H.; Zhao, Y. Light-triggered self-healing and shape-memory

(31)

(14) Meng, H.; Li, G. A review of stimuli-responsive shape memory polymer composites.

Polymer 2013, 54, 2199-2221.

(15) Fan, B.; Gillies, E. R. Self-Immolative Polymers. Encycl. Polym. Sci. Technol. 2015,

1-35.

(16) Sagi, A.; Weinstain, R.; Karton, N.; Shabat, D. Self-immolative polymers. J. Am.

Chem. Soc. 2008, 130, 5434-5435.

(17) Roth, M. E.; Green, O.; Gnaim, S.; Shabat, D. Dendritic, oligomeric, and polymeric

self-immolative molecular amplification. Chem. Rev. 2015, 116, 1309-1352.

(18) de Gracia Lux, C.; McFearin, C. L.; Joshi-Barr, S.; Sankaranarayanan, J.; Fomina, N.;

Almutairi, A. Single UV or Near IR triggering event leads to polymer degradation into

small molecules. ACS Macro Lett. 2012, 1, 922-926.

(19) Liu, G.; Wang, X.; Hu, J.; Zhang, G.; Liu, S. Self-immolative polymersomes for

high-efficiency triggered release and programmed enzymatic reactions. J. Am. Chem. Soc. 2014,

136, 7492-7497.

(20) Peterson, G. I.; Church, D. C.; Yakelis, N. A.; Boydston, A. J. 1, 2-oxazine linker as

a thermal trigger for self-immolative polymers. Polymer 2014, 55, 5980-5985.

(21) Esser-Kahn, A. P.; Sottos, N. R.; White, S. R.; Moore, J. S. Programmable

microcapsules from self-immolative polymers. J. Am. Chem. Soc. 2010, 132, 10266-10268.

(22) Diesendruck, C. E.; Peterson, G. I.; Kulik, H. J.; Kaitz, J. A.; Mar, B. D.; May, P. A.;

White, S. R.; Martínez, T. J.; Boydston, A. J.; Moore, J. S. Mechanically triggered

heterolytic unzipping of a low-ceiling-temperature polymer. Nat. Chem. 2014, 6, 623-628.

(23) DeWit, M. A.; Beaton, A.; Gillies, E. R. A reduction sensitive cascade biodegradable

linear polymer. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 3977-3985.

(24) Zhang, H.; Yeung, K.; Robbins, J. S.; Pavlick, R. A.; Wu, M.; Liu, R.; Sen, A.;

Phillips, S. T. Self-powered microscale pumps based on analyte-initiated depolymerization

reactions. Angew. Chem., Int. Ed. 2012, 51, 2400-2404.

(25) Phillips, S. T.; DiLauro, A. M. Continuous head-to-tail depolymerization: an emerging

concept for imparting amplified responses to stimuli-responsive materials. ACS Macro

(32)

(26) Fan, B. Polyglyoxylates: a new class of triggerable self-immolative polymers. 2014.

Electronic Thesis and Dissertation Repository. 2568. https://ir.lib.uwo.ca/etd/2568.

(27) Monks, T. J.; Jones, D. C. The metabolism and toxicity of quinones, quinonimines,

quinone methides, and quinone-thioethers. Curr. Drug Metab. 2002, 3, 425-438.

(28) Peterson, G. I.; Boydston, A. J. Kinetic analysis of mechanochemical chain scission

of linear poly (phthalaldehyde). Macromol. Rapid Commun. 2014, 35, 1611-1614.

(29) Fan, B.; Trant, J. F.; Wong, A. D.; Gillies, E. R. Polyglyoxylates: a versatile class of

triggerable self-immolative polymers from readily accessible monomers. J. Am. Chem.

Soc. 2014, 136, 10116-10123.

(30) Springsteen, G.; Yerabolu, J. R.; Nelson, J.; Rhea, C. J.; Krishnamurthy, R. Linked

cycles of oxidative decarboxylation of glyoxylate as protometabolic analogs of the citric

acid cycle. Nat. Commun. 2018, 9, 91.

(31) Lorenz, M. C.; Fink, G. R. The glyoxylate cycle is required for fungal virulence.

Nature 2001, 412, 83-86.

(32) Belloncle, B.; Bunel, C.; Menu-Bouaouiche, L.; Lesouhaitier, O.; Burel, F. Study of

the degradation of poly (ethyl glyoxylate): biodegradation, toxicity and ecotoxicity assays.

(33)

Chapter 2

2

Stimuli-responsive polymers (SRPs)

SRPs are polymers that can detect external signals and respond with changes in physical

properties (e.g., shape, color, solubility) or chemical structures (e.g., cleavage of side

groups or polymer backbone).1_{The chemical or physical property changes associated with}

SRPs endow them with a series of novel applications that cannot be achieved by traditional

materials.2-3 Therefore, SRPs have attracted significant attention from both academia and

industry. SRPs can be classified into two main categories according to their physical and

chemical property changes. However, depending on their degradability, SRPs can also be

separated into 1) general non-degradable SRPs (Figure 2.1a), and 2) stimuli-responsive and

degradable polymers (Figure 2.1b, 2.1c).

Figure 2.1 Schematic representations of SRPs: a) General non-degradable SRPs that

change in physical properties in response to a stimulus; b) SRPs that can entirely

degrade in response to a stimulus stoichiometrically; c) Self-immolative polymers

(SIPs) as a sub-class of SRPs that can depolymerize in response to a stimulus in an

amplified manner.

Over the past decade, stimuli-responsive and degradable polymers have evolved into two

different classes. The first class of SRPs can entirely degrade stoichiometrically in response

to stimuli (Figure 2.1b). However, a key limitation of these stimuli-responsive and

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complete degradation.4_{In addition, for each different stimulus, a completely new polymer}

backbone is usually required, which significantly increases the barrier for practical

applications. To address the limitations associated with conventional stimuli-responsive

and degradable polymers, new efforts have been directed to the amplified degradation of

polymeric materials in response to external stimuli in the past 10 years. This new

generation of stimuli-responsive and degradable polymers is usually referred as

“self-immolative polymers” (SIPs) (Figure 2.1c).5

This chapter systematically reviews the development and applications of

stimuli-responsive polymers (SRPs) in three main sections: 1) General non-degradable SRPs that

undergo changes in physical properties in response to external stimuli; 2) SRPs that can

entirely degrade stoichiometrically in response to stimuli; 3) Self-immolative polymers

(SIPs) as a sub-class of SRPs that can depolymerize in response to stimuli in an amplified

manner.

2.1 General non-degradable SRPs

The general non-degradable SRPs are polymers that can detect external stimuli and respond

in form of changes in physical properties such as shape, solubility, or color. The triggering

stimuli can be light, heat, specific chemicals or gases, or changes in pH, depending on the

responsive sites on polymer structures. Each stimulus has its own advantages and can

usually meet the demand for a specific application. For example, light can be applied in a

situation that does not require external additives and can be controlled spatiotemporally.

Heat can be readily applied from outside of polymer environment. Gases are easy to add

and remove, especially, in large volume operations and are of great interest in industrial

applications. This section reviews four representative non-degradable SRPs that can

respond to light, heat, pH changes, and gases.

2.1.1 Light-responsive polymers

Light has been one of the most extensively investigated stimuli for controlling polymer

properties and functions.6-8_{It can be easily applied and regulated remotely and possesses}

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external additives. Reversible light-controllable polymers have been heavily investigated

since the 1980s, and the potential applications of these polymers in optical-to-mechanical

conversion actuators and polymer nanoparticles for drug delivery have been explored.

In 1980, by incorporating aromatic azo chromophores as cross-linkers for rubbery

poly(ethyl acrylate), Eisenbach and coworkers demonstrated that the rubbery network

could contract and extend when it was irradiated with different wavelengths of light.9 This

photomechanical effect was believed to be caused by the conformational change resulting

from the trans-cis isomerization of the aromatic azo cross-linker. At the same time,

Riordan’s group observed the same effects when they incorporated the aromatic azo

functional group into polyamides, specifically,

poly(3,3’-zaodibenzoyl-trans-2,5-dimethylpiperazene) and poly(4,4’-azodibenzoyl-trans-poly(3,3’-zaodibenzoyl-trans-2,5-dimethylpiperazene).10 _The

photomechanical effect of aromatic azo compounds is an interesting phenomenon as it

allows the direct conversion of light into mechanical energy. Now, it has been well

established that aromatic azo compounds can undergo trans-cis isomerization when

irradiated by light with a wavelength of ~330-380 nm, and that this process is completely

reversible.11 The cis isomer can convert back to the trans isomer when the compound is

exposed to light with wavelength of ~420 nm, depending on the specific structure (Figure

2.2a)

Figure 2.2 Representative light-responsive molecules applied in stimuli-responsive

polymers: a) Cis-trans transformation of aromatic azo compounds, b) hydrophobic

spiropyran to hydrophilic merocyanine transformations under different wavelengths

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Following Eisenbach and Riordan’s pioneering work, much research was devoted to

aromatic azo-containing polymers in order to develop them as light-triggerable actuators.

For example, Zhao and coworkers recently reported a light-driven actuator based on an

azobenzene-containing liquid crystalline polymer network (Figure 2.3a).12 In this work,

they demonstrated that they could use UV light to generate mechanical force using light to

mechanical energy conversion and also light-triggered release of prestored strain energy in

a azobenzene-containing liquid crystalline polymer network that was synthesized from

4,4’-diglycidyloxyazobenzene and dodecanedioic acid. They achieved large and tunable

photoinduced contractile stress up to 7 MPa, which was much higher than previously

reported. Moreover, the azobenzene-containing polymer enabled continuous motions of

large rolling objects under irradiation of UV light (Figure 2.3b, c).

Figure 2.3 a) Synthesis procedure for the azobenzene liquid crystalline polymer

network; b) Schematic and c) photographs showing light-driven forward moving of a

“vehicle” equipped with a spring-like “motor”. (Reproduced with permission from

In addition to aromatic azo compounds, spiropyran (Figure 2.2b) is another well-known

photochromic molecule that has been widely studied in photo-responsive dynamic

materials. Spiropyran can respond to light irradiation (wavelength < 420 nm) and undergo

reversible isomerization from a colorless hydrophobic spiropyran to a colored hydrophilic

(37)

by light with wavelengths above 450 nm. Recognizing the possible application of this

molecule for drug delivery, in 2015 Liu’s group reported the fabrication of photochromic

vesicles that exhibited reversible changes in bilayer permeability upon triggering by

UV-Vis light irradiation (Figure 2.4).14 The photochromic amphiphilic block copolymer was

poly(ethylene glycol)-b-PSPA (PEG-b-PSPA) diblock copolymer, where SPA was a

spiropyran-based monomer containing a carbamate linkage. Upon self-assembly into

vesicles, the spiropyran moieties within the vesicle bilayers underwent reversible

photo-triggered isomerization between spiropyran and zwitterionic merocyanine states. The

microstructures of both vesicles were stabilized by multiple cooperative noncovalent

interactions including hydrogen bonding, π-π stacking, and zwitterionic interactions.

Interestingly, they found that the UV-actuated merocyanine vesicle possessed both

sustained release upon short UV irradiation and on-demand switchable release under

alternating UV-Vis light irradiation.

Figure 2.4 Photochromic polymersomes exhibiting photo-switchable and reversible

bilayer permeability. (Reproduced with permission from reference (14). Copyright

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2.1.2 Thermo-responsive polymers

Temperature change as a stimulus for polymers has also played a key role among all

available stimuli, as it can be readily applied from outside of the polymer environment.15

In particular, poly(N-isopropylacrylamide) (PNIPAM) is one of the most studied

thermo-responsive polymers that undergoes a phase transition in solution with temperature

changes.16 Once the temperature is above a certain limit, the polymer chain transforms

from a coil state to a globular state to minimize the free energy of the system. This leads to

the macroscopic phenomenon of an increase in solution turbidity. This temperature

associated phase transition is usually called the lower critical solution temperature (LCST).

Besides PNIPAM, there are several other polymers such as, poly[tri(ethylene glyocol)

monoethyl ether methacrylate] (PTEGMA),17 poly(dimethylaminoethyl methacrylate)

(PDMAEMA),18 and poly(2-isopropyl-2-oxazoline) (PIPOZ)19 that have the property of an

LCST as well (Figure 2.5). Because of this unique property, thermo-responsive polymers

have been widely studied for numerous applications such as drug delivery,20 catalysis,21

tissue engineering,22 and surface engineering.23

Figure 2.5 Chemical structures of some typical thermo-responsive polymers.

In 2013, Liu and coworkers reported a temperature-controllable dual water/oil on-off

switch mesh allowing the separation of water and oil by controlling the temperature.23_The

steel mesh was coated with block copolymer poly(methyl methacrylate)

(PMMA)-b-PNIPAM. Due to the hydrophilic-hydrophobic transition around the LCST of PNIPAM

and the resultant surface roughness change, the mesh could be open to water and closed to

(39)

2.6). This work provided a smart solution to the controllable separation of water and oil

mixtures.

Figure 2.6 a) Temperature dependence of water and oil contact angles for a

PMMA-b-PNIPAM film; b) Reversible water and oil contact angle transition of block

copolymer film at different temperatures; c) Diagram of reversible formation of

intermolecular hydrogen bonding between PNIPAM chains and water below and

WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

2.1.3 pH-responsive polymers

Change in pH is another stimulus that can trigger the change of polymer physical properties.

For some organic functional groups, such as organic acids, pyridines, and amines,

environmental pH changes lead to the protonation or deprotonation of these functional

groups and consequently result in solubility changes of these molecules. Therefore,

polymers containing these functional groups also exhibit pH-dependent solubility.

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poly(2-vinylpyridine) (P2VP) (pKa = 3.0), and poly(2-N,N’-dimethylaminoethyl methacrylate)

(PDMAEMA) (pKa= 7.5) (Figure 2.7).

Figure 2.7 Chemical structures of some representative pH-responsive polymers.

Based on the properties of pH-responsive polymers, in 2014 Kim and coworkers reported

a versatile platform for a highly stable and wide-range pH sensor that could respond to pH

variations from 1 to 7.24_{This sensor platform consisted of the pH-responsive polymers}

PAA and P2VP, and quantum dots (QDs). The PAA chain was grafted onto the surface of

blue-colored cadmium sulfide/zinc sulfide QDs, and the P2VP chain was grafted onto the

surface of orange-colored cadmium selenide/zinc sulfide QDs. The hybrids were deposited

on the surface of single graphene oxide (GO) sheets via π-π staking interactions between

the pyrene functional groups on the polymer termini and the basal plane of the GO surfaces.

The distances between the two color-emitting QDs and the GO were controlled by the

linker polymers PAA and P2VP. The sensing scheme is shown in Figure 2.8. Specifically,

when the pH was lower than 3, the protonation of P2VP led to the swelling and extension

of polymer chains, while the PAA chains were protonated and less soluble in water,

resulting in their collapse and attachment to the GO. This led to the quenching of blue

colored QDs, and consequently the orange colored QDs on P2VP dominated the emission.

When the pH was higher than 4.5, the deprotonation of PAA led to the swelling and

extension of PAA and the collapse of P2VP, so emission from the blue QDs dominated.

When the pH was between these two values, both QDs emitted light and therefore white

(41)

Figure 2.8 Structures of a) P2VP-QD and b) PAA-QD; c) Schematic illustration of the

conformation and behavior of QD-GO at a given pH value. (Reproduced with

In addition to pH sensors, pH-responsive polymers have also been exploited to deliver

drugs or genes to specific tissues and trigger the release of payloads at target sites. The

basic theory behind this application is that healthy tissues have a pH of 7.4, whereas in

inflamed tissues or tumors the environment is slightly acidic. These pH variations can lead

to solubility and morphology changes of pH-responsive polymers, enabling the delivery of

the payload.25-26

2.1.4 Gas-responsive polymers

Gases can be easily added and removed from a system, especially, in large volume

operations. Therefore, gaseous triggers are of great interest in industrial applications.

Several gaseous triggers have been reported so far including CO2,27 CO,28 NO,29 and H2S.30

Numerous applications have been explored for these gas-responsive polymers, such as drug

delivery vehicles, cell signaling systems, microgels, and nanoreactors.31 As a non-toxic and

abundant gas, CO2 is the most studied gas trigger for gas-responsive polymers. A number

of CO2-reactive functional groups have been explored including tertiary amines, amidines,

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as those in PDMAEMA (Figure 2.7) are the most frequently explored because the pKa

values of polymeric tertiary amines typically range from 6.5 to 8.1.34_{The protonation and}

deprotonation of this class of polymers can readily occur upon the addition or removal of

CO2 through bubbling of CO2 or an inert gas (nitrogen or argon) respectively, resulting in

solubility changes of the polymer.

For example, in 2017 Zhao and coworkers reported CO2-responsive polymer nanoparticles

and micellar aggregates as gas-controlled nanoreactors for gold nanoparticle synthesis with

the capability to tune the gold nanoparticle size and formation rate.35 The nanoparticles

were prepared from the random copolymer poly{(N,N’-dimethylaminoethyl

methacrylate)-co-4-methyl-[7-(methacryloyl)oxyl-ethyl-oxyl]coumarin} (P(DMAEMA-co-CMA).

Tadpole-like single-chain nanoparticles were prepared from an amphiphilic block

copolymer of PS-b-P(DMAEMA-co-CMA). (PS represents polystyrene) (Figure 2.9).

Both particles underwent reversible swelling/shrinking with CO2/N2 stimulation. In

addition, they found the rate of gold nanoparticle formation using these particles as

nanoreactors increased under CO2 stimulation and slowed down by bubbling with N2. CO2

-induced swelling likely provided easier access of AuCl4 − counterions into the nanoreactors

for association with protonated amine groups, and residual non-protonated tertiary amine

groups led to AuCl4 − in-situ reduction to zerovalent gold. They also demonstrated that the

size of the gold nanoparticles could be controlled by the amount of CO2 in solution via the

(43)

Figure 2.9 Schematic illustration of: a) Preparation of P(DMAEMA-co-CMA)

single-chain nanoparticles through intrasingle-chain photo-cross-linking and the gas-switchable

size change of nanoparticle in aqueous solution; b) Preparation of tadpole-like

PS-b-P(DMAEMA-co-CMA) nanoparticles and their gas-responsive self-assembled

micellar assemblies. (Reproduced with permission from reference (35). Copyright

2017 American Chemical Society.)

2.2 Stimuli-responsive and degradable polymers

In addition to the physical property changes that occur in non-degradable SRPs as

described above, there is another class of SRPs that can undergo complete backbone

degradation in response to specific stimuli. In general, there are three major class of

stimuli-responsive and degradable polymers including 1) acid-degradable polymers; 2)

redox-degradable polymers; 3) photo-degradable polymers. In this section, examples and

applications for these three classes of stimuli-responsive and degradable polymers will be

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2.2.1 Acid-degradable polymers

Acid-responsive and degradable polymers are usually designed with the incorporation of

acid-sensitive functional groups such as acetals, ketals, imines, and hydrazones (Figure

2.10).36 Despite the structural diversity of these groups, they all tend to be stable or have

slow degradation at neutral pH and are prone to degrade much faster at acidic pH. These

acid-responsive and degradable polymers are commonly used to form drug delivery

vehicles for the targeted and triggered release of therapeutics, as healthy tissues have a pH

around 7.4, whereas inflamed tissues or tumors have mildly acidic pHs ranging from

5.7-7.8. The endosomal and lysosomal compartments of cells also have acidic pHs ranging

from 4.5-5.5.3,36-37

Figure 2.10 Common acid-degradable functional groups and their degradation

products.

The degradation of acetals and ketals has been a subject of interest since 1960s,38-39 and

has attracted significant attention in the past decades, as these moieties yield charge-neutral

and potentially non-toxic products upon cleavage.40 In addition, the hydrolysis rate is

linearly proportional to the H+ concentration, ensuring a predictable response to pH

changes. Therefore, acetal- and ketal-based polymers have been the most widely studied